Monocyte Chemotactic Protein-1 in Proliferative Vitreoretinal Disorders

El‐Asrar, Ahmed M. Abu; Damme, Jo Van; Put, Willy; Veckeneer, Marc; Dralands, L; Billiau, Alfons; Missotten, Luc

doi:10.1016/s0002-9394(14)71072-4

Cited by 91 publications

(64 citation statements)

References 42 publications

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“…50,51 The study by Hazra et al 5 found that monocytes expressing the CCL2 receptor (CCR2) are present in increased numbers in the circulation and are found to accumulate in the retina of streptozotocin-diabetic mice, implicating the CCL2-CCR2 axis in the development of DR.…”

Section: Retinal Overexpression Of Ace2 May Suppress Proinflammatory mentioning

confidence: 99%

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

Dominguez

Caballero

et al. 2016

The American Journal of Pathology

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Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)eACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein (GFP)echimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrowederived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP þ cells was used to measure leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 AE 1.4; ACE2 diabetic, 6.4 AE 0.9 per mm 2 ) and partially reversed (reversal cohort: untreated diabetic, 15.7 AE 1.9; ACE2 diabetic, 6.5 AE 1.2 per mm 2 ) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80 þ ) (prevention cohort: untreated diabetic, 24.2 AE 6.7; ACE2 diabetic, 2.5 AE 1.6 per mm 2 ; reversal cohort: untreated diabetic, 56.8 AE 5.2; ACE2 diabetic, 5.6 AE 2.3 per mm 2 ). In both study cohorts, intracapillary bone marrowederived cells, indicative of leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system. (Am J Pathol 2016, 186: 1688e1700; http://dx

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Section: Retinal Overexpression Of Ace2 May Suppress Proinflammatory mentioning

confidence: 99%

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

Dominguez

Caballero

et al. 2016

The American Journal of Pathology

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“…In recent years, accumulating evidence suggests that inflammation is a key event in the pathogenesis of diabetic vascular complications (Abu El-Asrar et al 1997, Mitamura et al 2001, Hernández et al 2005. In early stages of diabetic retinopathy, expression of pro-inflammatory cytokines, adhesion molecules, and chemokines is significantly up-regulated in the retina, in parallel with breakdown of blood-retina barrier and increased vascular permeability (Joussen et al 2004, Zhang et al 2006.…”

Section: Introductionmentioning

confidence: 99%

“…The critical role of MCP-1 in diabetic vascular complications has been intensively studied and established in cardiovascular (macrovascular) diseases in diabetes (Sonoki et al 2002, Renier et al 2003. In diabetic retinopathy, MCP-1 levels in the vitreous are significantly elevated in patients with proliferative diabetic retinopathy (Abu El-Asrar et al 1997, Mitamura et al 2001, Hernández et al 2005. In streptozotocin (STZ)-induced diabetic animals, expression of MCP-1 is also up-regulated in the retina and correlates with increased retinal vascular permeability (Zhang et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein

Zhang¹,

Wang²,

Dashti³

et al. 2008

Journal of Molecular Endocrinology

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Oxidized and/or glycated low-density lipoprotein (LDL) may mediate capillary injury in diabetic retinopathy. The mechanisms may involve pro-inflammatory and pro-oxidant effects on retinal capillary pericytes. In this study, these effects, and the protective effects of pigment epithelium-derived factor (PEDF), were defined in a primary human pericyte model. Human retinal pericytes were exposed to 100 mg/ml native LDL (N-LDL) or heavily oxidized glycated LDL (HOG-LDL) with or without PEDF at 10-160 nM for 24 h. To assess pro-inflammatory effects, monocyte chemoattractant protein-1 (MCP-1) secretion was measured by ELISA, and nuclear factor-kB (NF-kB) activation was detected by immunocytochemistry. Oxidative stress was determined by measuring intracellular reactive oxygen species (ROS), peroxynitrite (ONOO K ) formation, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) production. The results showed that MCP-1 was significantly increased by HOG-LDL, and the effect was attenuated by PEDF in a dose-dependent manner. PEDF also attenuated the HOG-LDL-induced NF-kB activation, suggesting that the inhibitory effect of PEDF on MCP-1 was at least partially through the blockade of NF-kB activation. Further studies demonstrated that HOG-LDL, but not N-LDL, significantly increased ONOO K formation, NO production, and iNOS expression. These changes were also alleviated by PEDF. Moreover, PEDF significantly ameliorated HOG-LDL-induced ROS generation through up-regulation of superoxide dismutase 1 expression. Taken together, these results demonstrate proinflammatory and pro-oxidant effects of HOG-LDL on retinal pericytes, which were effectively ameliorated by PEDF. Suppressing MCP-1 production and thus inhibiting macrophage recruitment may represent a new mechanism for the salutary effect of PEDF in diabetic retinopathy and warrants more studies in future.

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“…Because the consensus sequence for HIF-1 transcription factor is present in the promoter of iNOS (Melillo et al, 1995), HIF could be responsible for iNOS induction in the ischemic retina. In recent years, accumulating evidence suggests that inflammation is a key event in the pathogenesis of diabetic vascular complications (Abu el-Asrar et al, 1997;Mitamura et al, 2001;Herná ndez et al, 2005). During diabetic retinopathy, the expression of iNOS is up-regulated and is thought to play a key role in the pathogenesis of retinal neovascularization.…”

mentioning

confidence: 99%

Pleiotropic Effects of YC-1 Selectively Inhibit Pathological Retinal Neovascularization and Promote Physiological Revascularization in a Mouse Model of Oxygen-Induced Retinopathy

DeNiro¹,

Al-Halafi²,

Almohanna³

et al. 2009

Mol Pharmacol

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Vascular endothelial growth factor (VEGF) and inducible nitricoxide synthase (iNOS) have been implicated in ischemia-induced retinal neovascularization. Retinal ischemia has been shown to induce VEGF and iNOS expression. It has been postulated that one of the crucial consequences of iNOS expression in the ischemic retina is the inhibition of angiogenesis. Furthermore, iNOS was shown to be overexpressed in Mü ller cells from patients with diabetic retinopathy. YC-1, a small molecule inhibitor of hypoxia-inducible factor (HIF)-1␣, has been shown to inhibit iNOS expression in various tissue models. Our aim was to assess the pleiotropic effects of YC-1 in an oxygen-induced retinopathy (OIR) mouse model and evaluate its therapeutic potential in HIF-1-and iNOS-mediated retinal pathologies. Dual-injections of YC-1 into the neovascular retinas decreased the total retinopathy score, inhibited vaso-obliteration and pathologic tuft formation, and concomitantly promoted physiological retinal revascularization, compared with dimethyl sulfoxide (DMSO)-treated group. Furthermore, YC-1-treated retinas exhibited a marked increase in immunoreactivities for CD31 and von Willebrand factor and displayed significant inhibition in HIF-1␣ protein expression. Furthermore, YC-1 down-regulated VEGF, erythropoietin, endothelin-1, matrix metalloproteinase-9, and iNOS message and protein levels. When hypoxic Mü ller and neuoroglial cells were treated with YC-1, iNOS mRNA and protein levels were reduced in a dosedependent fashion. We demonstrate that YC-1 inhibits pathological retinal neovascularization by exhibiting antineovascular activities, which impaired ischemia-induced expression of HIF-1 and its downstream angiogenic molecules. Furthermore, YC-1 enhanced physiological revascularization of the retinal vascular plexuses via the inhibition of iNOS mRNA and protein expressions. The pleiotropic effects of YC-1 allude to its possible use as a promising therapeutic iNOS inhibitor candidate for the treatment of retinal neovascularization.Retinal neovascularization (NV) is the major cause of severe vision loss and irreversible blindness in developed countries, affecting people of all ages (Lee et al., 1998). These clinical and pathologic manifestations occur in diabetic retinopathy, retinopathy of prematurity (ROP), age-related macular degeneration and retinal vein occlusion. The early stages of retinopathy result from retinal ischemia as a result of nonperfusion of the retina or a decrease in oxygen tension (Barinapa, 1995). In the late stages, the ischemia-induced pathologic growth of new blood vessels can cause catastrophic loss of vision.

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Monocyte Chemotactic Protein-1 in Proliferative Vitreoretinal Disorders

Cited by 91 publications

References 42 publications

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein

Pleiotropic Effects of YC-1 Selectively Inhibit Pathological Retinal Neovascularization and Promote Physiological Revascularization in a Mouse Model of Oxygen-Induced Retinopathy

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